Lack of correlation between the optimal glycaemic control and coronary micro vascular dysfunction in patients with diabetes mellitus: a cross sectional study.

Background Coronary microvascular dysfunction (CMD) is associated with cardiovascular events in type 2 diabetes mellitus (T2DM). Optimal glycaemic control does not always preclude future events. We sought to assess the effect of the current target of HBA1c level on the coronary microcirculatory function and identify predictive factors for CMD in T2DM patients. Methods We studied 100 patients with T2DM and 214 patients without T2DM. All of them with a history of chest pain, non-obstructive angiograms and a direct assessment of coronary blood flow increase in response to adenosine and acetylcholine coronary infusion, for evaluation of endothelial independent and dependent CMD. Patients with T2DM were categorized as having optimal (HbA1c < 7 %) vs. suboptimal (HbA1c ≥ 7 %) glycaemic control at the time of catheterization. Results Baseline characteristics and coronary endothelial function parameters differed significantly between T2DM patients and control group. The prevalence of endothelial independent CMD (29.8 vs. 39.6 %, p = 0.40) and dependent CMD (61.7 vs. 62.2 %, p = 1.00) were similar in patients with optimal vs. suboptimal glycaemic control. Age (OR 1.10; CI 95 % 1.04–1.18; p < 0.001) and female gender (OR 3.87; CI 95 % 1.45–11.4; p < 0.01) were significantly associated with endothelial independent CMD whereas glomerular filtrate (OR 0.97; CI 95 % 0.95–0.99; p < 0.05) was significantly associated with endothelial dependent CMD. The optimal glycaemic control was not associated with endothelial independent (OR 0.60, CI 95 % 0.23–1.46; p 0.26) or dependent CMD (OR 0.99, CI 95 % 0.43–2.24; p = 0.98). Conclusions The current target of HBA1c level does not predict a better coronary microcirculatory function in T2DM patients. The appropriate strategy for prevention of CMD in T2DM patients remains to be addressed. Keywords: Endothelial dysfunction; Diabetes mellitus; Coronary microcirculation

Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients

RESUME : Objectif: Le glioblastome multiforme (GBM) est la tumeur cérébrale maligne la plus agressive qui conduit au décès de la majorité des patients moins d'une année après le diagnostic. La plupart des agents chimiothérapeutiques actuellement disponibles ne traversent pas la barrière hémato¬encéphalique et ne peuvent par conséquent pas être utilisés pour ce type de tumeur. Le Temozolomide (TMZ) est un nouvel agent alkylant récemment développé pour le traitement des gliomes malins. A ce jour, très peu d'informations sont disponibles sur la pénétration intra-cérébrale de cet agent. Au cours d'une étude pilote de phase II menée auprès de 64 patients atteints de GBM, l'administration précoce de TMZ combinée à une radiothérapie standard (RT) afin d'intervenir au plus tôt dans l'évolution de la maladie, a permis de prolonger la survie de ces patients, résultat qui pu être confirmé par la suite lors de l'étude randomisée de phase III. L'objectif de cette étude a été de déterminer les paramètres pharmacocinétique du TMZ dans le plasma et le liquide céphalo-rachidien (LCR), d'évaluer l'influence de certains facteurs individuels (âge, sexe, surface corporelle, fonction rénale/hépatique, co-médications, RT concomitante) sur ces différents paramètres, et enfin d'explorer la relation existant entre l'exposition au TMZ et certains marqueurs cliniques d'efficacité et de toxicité. Matériel et Méthode: Les concentrations de TMZ ont été mesurées par chromatographie liquide à haute performance (HPLC) dans le plasma et le LCR de 35 patients atteints de GBM nouvellement diagnostiqués (étude pilote) ou de gliomes malins en récidive (étude récidive). L'analyse pharmacocinétique de population a été réalisée à l'aide du programme NONMEM. L'exposition systémique et cérébrale, définie par les AUC (Area Under the time-concentration Curve) dans le plasma et le LCR, a été estimée pour chaque patient et corrélée à la toxicité, la survie ainsi que la survie sans progression tumorale. Résultats: Un modèle à 1 compartiment avec une cinétique d'absorption et de transfert Kplasma -> LCR de ordre a été retenu afin de décrire le profil pharmacocinétique du TMZ. Les valeurs moyennes de population ont été de 10 L/h pour la clairance, de 30.3 L pour le volume de distribution, de 2.1 h pour la 1/2 vie d'élimination, de 5.78 hE-1 pour la constante d'absorption, de 7.2 10E4 hE-1 pour Kplasma->LCR et de 0.76 hE-1 pour KLCR plasma. La surface corporelle a montré une influence significative sur la clairance et le volume de distribution, alors que le sexe influence la clairance uniquement. L'AUC mesurée dans le LCR représente ~20% de celle du plasma et une augmentation de 15% de Kplasma->LCR a été observée lors du traitement concomitant de radiochimiothérapie. Conclusions: Cette étude est la première analyse pharmacocinétique effectuée chez l'homme permettant de quantifier la pénétration intra-cérébrale du TMZ. Le rapport AUC LCR/AUC Plasma a été de 20%. Le degré d'exposition systémique et cérébral au TMZ ne semble pas être un meilleur facteur prédictif de la survie ou de la tolérance au produit que ne l'est la dose cumulée seule. ABSTRACT Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of ma¬lignant brain tumors. The purpose was to assess TNIZ phar¬macokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covari¬ates and to explore relationships between systemic or cere¬bral drug exposure and clinical outcomes. Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacoki¬netic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area un¬der the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (VD), 30.3 liters; absorption constant rate, 5.8 hE-1; elimination half-time, 2.1 h; transfer rate from plasma to CSF (Kplasma->CSF), 7.2 x 10E-4hE-1 and the backwards rate, 0.76hE-1. Body surface area signifi¬cantly influenced both clearance and VD, and clearance was sex dependent. The AU CSF corresponded to 20% of the AUCplasma. A trend toward an increased K plasma->CSF of 15% was observed in case of concomitant radiochemo-therapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC CSF/ AUC plasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

Exploring unfrequent events with accelerated molecular dynamics simulations: from photochemistry to drug design

La meva incorporació al grup de recerca del Prof. McCammon (University of California San Diego) en qualitat d’investigador post doctoral amb una beca Beatriu de Pinós, va tenir lloc el passat 1 de desembre de 2010; on vaig dur a terme les meves tasques de recerca fins al darrer 1 d’abril de 2012. El Prof. McCammon és un referent mundial en l’aplicació de simulacions de dinàmica molecular (MD) en sistemes biològics d’interès humà. La contribució més important del Prof. McCammon en la simulació de sistemes biològics és el desenvolupament del mètode de dinàmiques moleculars accelerades (AMD). Les simulacions MD convencionals, les quals estan limitades a l’escala de temps del nanosegon (~10-9s), no son adients per l’estudi de sistemes biològics rellevants a escales de temps mes llargues (μs, ms...). AMD permet explorar fenòmens moleculars poc freqüents però que son clau per l’enteniment de molts sistemes biològics; fenòmens que no podrien ser observats d’un altre manera. Durant la meva estada a la “University of California San Diego”, vaig treballar en diferent aplicacions de les simulacions AMD, incloent fotoquímica i disseny de fàrmacs per ordinador. Concretament, primer vaig desenvolupar amb èxit una combinació dels mètodes AMD i simulacions Car-Parrinello per millorar l’exploració de camins de desactivació (interseccions còniques) en reaccions químiques fotoactivades. En segon lloc, vaig aplicar tècniques estadístiques (Replica Exchange) amb AMD en la descripció d’interaccions proteïna-lligand. Finalment, vaig dur a terme un estudi de disseny de fàrmacs per ordinador en la proteïna-G Rho (involucrada en el desenvolupament de càncer humà) combinant anàlisis estructurals i simulacions AMD. Els projectes en els quals he participat han estat publicats (o estan encara en procés de revisió) en diferents revistes científiques, i han estat presentats en diferents congressos internacionals. La memòria inclosa a continuació conté més detalls de cada projecte esmentat.

Collage, a Collaborative Learning Design Editor Based on Patterns

This paper introduces Collage, a high-level IMS-LD compliant authoring tool that is specialized for CSCL (Computer-Supported Collaborative Learning). Nowadays CSCL is a key trend in elearning since it highlights the importance of social interactions as an essential element of learning. CSCL is an interdisciplinary domain, which demands participatory design techniques that allow teachers to get directly involved in design activities. Developing CSCL designs using LD is a difficult task for teachers since LD is a complex technical specification and modelling collaborative characteristics can be tricky. Collage helps teachers in the process of creating their own potentially effective collaborative Learning Designs by reusing and customizing patterns, according to the requirements of a particular learning situation. These patterns, called Collaborative Learning Flow Patterns (CLFPs), represent best practices that are repetitively used by practitioners when structuring the flow of (collaborative) learning activities. An example of an LD that can be created using Collage is illustrated in the paper. Preliminary evaluation results show that teachers, with experience in CL but without LD knowledge, can successfully design real collaborative learning experiences using Collage.

A multicase study for the evaluation of a pattern-based visual design process for collaborative learning

Collage is a pattern-based visual design authoring tool for the creation of collaborative learning scripts computationally modelled with IMS Learning Design (LD). The pattern-based visual approach aims to provide teachers with design ideas that are based on broadly accepted practices. Besides, it seeks hiding the LD notation so that teachers can easily create their own designs. The use of visual representations supports both the understanding of the design ideas and the usability of the authoring tool. This paper presents a multicase study comprising three different cases that evaluate the approach from different perspectives. The first case includes workshops where teachers use Collage. A second case implies the design of a scenario proposed by a third-party using related approaches. The third case analyzes a situation where students follow a design created with Collage. The cross-case analysis provides a global understanding of the possibilities and limitations of the pattern-based visual design approach.

Optimal Contracts, Adverse Selection, and Social Preferences: An Experiment

It has long been standard in agency theory to search for incentive-compatible mechanisms on the assumption that people care only about their own material wealth. However, this assumption is clearly refuted by numerous experiments, and we feel that it may be useful to consider nonpecuniary utility in mechanism design and contract theory. Accordingly, we devise an experiment to explore optimal contracts in an adverse-selection context. A principal proposes one of three contract menus, each of which offers a choice of two incentive-compatible contracts, to two agents whose types are unknown to the principal. The agents know the set of possible menus, and choose to either accept one of the two contracts offered in the proposed menu or to reject the menu altogether; a rejection by either agent leads to lower (and equal) reservation payoffs for all parties. While all three possible menus favor the principal, they do so to varying degrees. We observe numerous rejections of the more lopsided menus, and approach an equilibrium where one of the more equitable contract menus (which one depends on the reservation payoffs) is proposed and agents accept a contract, selecting actions according to their types. Behavior is largely consistent with all recent models of social preferences, strongly suggesting there is value in considering nonpecuniary utility in agency theory.

Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function.

Protective adaptive immune responses rely on TCR-mediated recognition of Ag-derived peptides presented by self-MHC molecules. However, self-Ag (tumor)-specific TCRs are often of too low affinity to achieve best functionality. To precisely assess the relationship between TCR-peptide-MHC binding parameters and T cell function, we tested a panel of sequence-optimized HLA-A(*)0201/NY-ESO-1(157-165)-specific TCR variants with affinities lying within physiological boundaries to preserve antigenic specificity and avoid cross-reactivity, as well as two outliers (i.e., a very high- and a low-affinity TCR). Primary human CD8 T cells transduced with these TCRs demonstrated robust correlations between binding measurements of TCR affinity and avidity and the biological response of the T cells, such as TCR cell-surface clustering, intracellular signaling, proliferation, and target cell lysis. Strikingly, above a defined TCR-peptide-MHC affinity threshold (K(D) < approximately 5 muM), T cell function could not be further enhanced, revealing a plateau of maximal T cell function, compatible with the notion that multiple TCRs with slightly different affinities participate equally (codominantly) in immune responses. We propose that rational design of improved self-specific TCRs may not need to be optimized beyond a given affinity threshold to achieve both optimal T cell function and avoidance of the unpredictable risk of cross-reactivity.

Cost system design and cost management in the Spanish public sector

Cost systems have been shown to have developed considerably in recent years andactivity-based costing (ABC) has been shown to be a contribution to cost management,particularly in service businesses. The public sector is composed to a very great extentof service functions, yet considerably less has been reported of the use of ABC tosupport cost management in this sector.In Spain, cost systems are essential for city councils as they are obliged to calculate thecost of the services subject to taxation (eg. waste collection, etc). City councils musthave a cost system in place to calculate the cost of services, as they are legally requirednot to profit , from these services.This paper examines the development of systems to support cost management in theSpanish Public Sector. Through semi-structured interviews with 28 subjects within oneCity Council it contains a case study of cost management. The paper contains extractsfrom interviews and a number of factors are identified which contribute to thesuccessful development of the cost management system.Following the case study a number of other City Councils were identified where activity-based techniques had either failed or stalled. Based on the factors identified inthe single case study a further enquiry is reported. The paper includes a summary usingstatistical analysis which draws attention to change management, funding and politicalincentives as factors which had an influence on system success or failure.

Optimal regulation of a fully insured deposit banking system

We analyze risk sensitive incentive compatible deposit insurancein the presence of private information when the market value of depositinsurance can be determined using Merton's (1997) formula. We show that,under the assumption that transferring funds from taxpayers to financialinstitutions has a social cost, the optimal regulation combines differentlevels of capital requirements combined with decreasing premia on depositinsurance. On the other hand, it is never efficient to require the banksto hold riskless assets, so that narrow banking is not efficient. Finally,chartering banks is necessary in order to decrease the cost of asymmetricinformation.

Optimal monetary and fiscal policy in a currency union

We lay out a tractable model for fiscal and monetary policy analysis in a currency union, and study its implications for the optimal design of such policies. Monetary policy is conducted by a common central bank, which sets the interest rate for the union as a whole. Fiscal policy is implemented at the countrylevel, through the choice of government spending. The model incorporates country-specific shocks and nominal rigidities. Under our assumptions, the optimal cooperative policy arrangement requires that inflation be stabilized at the union level by the common central bank, while fiscal policy is used by each country for stabilization purposes. By contrast, when the fiscal authorities act in a non-coordinated way, their joint actions lead to a suboptimal outcome, and make the common central bank face a trade-off between inflation and output gap stabilization at the union level.

Costly search and design

Firms compete by choosing both a price and a design from a family of designs thatcan be represented as demand rotations. Consumers engage in costly sequential searchamong firms. Each time a consumer pays a search cost he observes a new offering. Anoffering consists of a price quote and a new good, where goods might vary in the extentto which they are good matches for the consumer. In equilibrium, only two design-styles arise: either the most niche where consumers are likely to either love or loathethe product, or the broadest where consumers are likely to have similar valuations. Inequilibrium, different firms may simultaneously offer both design-styles. We performcomparative statics on the equilibrium and show that a fall in search costs can lead tohigher industry prices and profits and lower consumer surplus. Our analysis is relatedto discussions of how the internet has led to the prevalence of niche goods and the"long tail" phenomenon.

Optimal second-degree price discrimination and arbitrage: On the role of asymetric information among buyers

The traditional theory of monopolistic screening tackles individualself-selection but does not address the possibility that buyers couldform a coalition to coordinate their purchases and to reallocate thegoods. In this paper, we design the optimal sale mechanism which takesinto account both individual and coalition incentive compatibilityfocusing on the role of asymmetric information among buyers. We showthat when a coalition of buyers is formed under asymmetric information,the monopolist can do as well as when there is no coalition. Although inthe optimal sale mechanism marginal rates of substitution are notequalized across buyers (hence there exists room for arbitrage), theyfail to realize the gains from arbitrage because of the transaction costsin coalition formation generated by asymmetric information.

Competition and cost overruns. Optimal misspecification of procurement contracts

Most cases of cost overruns in public procurement are related to important changes in the initial project design. This paper deals with the problem of design specification in public procurement and provides a rationale for design misspecification. We propose a model in which the sponsor decides how much to invest in design specification and awards competitively the project to a contractor. After the project has been awarded the sponsor engages in bilateral renegotiation with the contractor, in order to accommodate changes in the initial project s design that new information makes desirable. When procurement takes place in the presence of horizontally differentiated contractors, the design s specification level is seen to affect the resulting degree of competition. The paper highlights this interaction between market competition and design specification and shows that the sponsor s optimal strategy, when facing an imperfectly competitive market supply, is to underinvest in design specification so as to make significant cost overruns likely. Since no such misspecification occurs in a perfectly competitive market, cost overruns are seen to arise as a consequence of lack of competition in the procurement market.

Optimal contracts, adverse selection and social preferences: An experiment

It has long been standard in agency theory to search for incentive-compatible mechanisms on the assumption that people care only about their own material wealth. However, this assumption is clearly refuted by numerous experiments, and we feel that it may be useful to consider nonpecuniary utility in mechanism design and contract theory. Accordingly, we devise an experiment to explore optimal contracts in an adverse-selection context. A principal proposes one of three contract menus, each of which offers a choice of two incentive-compatible contracts, to two agents whose types are unknown to the principal. The agents know the set of possible menus, and choose to either accept one of the two contracts offered in the proposed menu or to reject the menu altogether; a rejection by either agent leads to lower (and equal) reservation payoffs for all parties. While all three possible menus favor the principal, they do so to varying degrees. We observe numerous rejections of the more lopsided menus, and approach an equilibrium where one of the more equitable contract menus (which one depends on the reservation payoffs) is proposed and agents accept a contract, selecting actions according to their types. Behavior is largely consistent with all recent models of social preferences, strongly suggesting there is value in considering nonpecuniary utility in agency theory.